Pain and analgesia
Pain has been defined in a variety of ways. For example, pain can be defined as the perception by a subject of noxious stimuli that produces a withdrawal reaction by the subject. The most commonly experienced form of pain may be defined as the effect of a stimulus on nerve endings, which results in the transmission of impulses to the cerebrum. This somatic sensation and normal function of pain, referred to as nociception or nociceptive pain, informs the organism of impending tissue damage. Somatic and visceral free nerve endings, termed nociceptors, initially process such pain signals.
Despite numerous definitions, the brain pathways governing the perception of pain are not completely understood. Sensory afferent synaptic connections to the spinal cord, so-called "nociceptive pathways", however, have been documented in some detail. The nociceptive pathway, which exists for protection of the organism (such as the pain experienced in response to a burn), is inactive. Activity is initiated by the application of a high intensity, potentially damaging stimulus. This stimulus serves to depolarize certain classes of afferent (sensory) axons of the small unmyelinated category, designed C fibers.
The signal carried by the C fibers travels up the peripheral nerve and into the spinal cord where synapses are made on second order and higher order neurons, which then transmit the pain signal up the spinal cord in the spinothalamic tract ending in the thalamus. Polysynaptic junctions in the dorsal horn of the spinal cord are involved in the relay and modulation of sensations of pain to various regions of the brain, including the periaqueductal grey region. The ventrolateral and ventromedial thalamic nuclei project to the cortex where the pain is then processed with regard to localization and other integrative characteristics.
Opioid Analgesia
Analgesia, or the reduction of pain perception, can be effected directly by decreasing transmission along such nociceptive pathways.
Analgesic opiates are thought to act by mimicking the effects of endorphin or enkephalin peptide-containing neurons, which synapse presynaptically at the C-fiber terminal and which, when they fire, inhibit release of substance P from the C-fiber. Descending pathways from the brain are also inhibitory to C-fiber firing. Thus, CNS-mediated analgesia leads to an overall inhibition of the pain transmission.
Agents that selectively block an animal's response to a strong stimulus without obtunding general behavior or motor function is referred to as an analgesic. Opiates, via interaction with specific receptors in the brain and spinal cord, are able to block the release of transmitters from central terminals (Yaksh et al. (1988) In: Progress in Brain Research, Vol. 77, Chapter 28, Elsevier Science Pub., B.V. pp. 371-94)). They are thus able to increase the intensity of the peripheral stimulus necessary to produce a given pain state. Accordingly, these agents are referred to as analgesics.
Opiates receptors and opiate side effects
Central opiate receptors (in brain and spinal cord) appear to mediate the effects of systemically administered opiates. Three principal classes of opiate receptors have been identified: .mu., .kappa. and .delta. (Yaksh, T. L.: Eur. J. Anaesthesiol. 1:201-243, 1984). The use of selective agonists and antagonists have demonstrated that these receptors also appear to mediate peripheral opioid effects. The central and peripheral actions activities of opiates are an important component of their therapeutic utility. It appears that after systemic delivery of opiates such as morphine, the primary effect may be mediated by both sites of action.
On the other hand, many of the principal drawbacks of systemic opiates are the results of their actions within the brain. These actions include sedation, depression of respiration, constipation, nausea and emesis, abuse liability and the development of addiction (Yaksh, Eur. J. Anaesthesiol. 1:171-199, 1984). These side effects serve to limit the utility of opiates for controlling post injury pain. Addiction liability can occur secondary to medical uses of the drug where the central effects lead to an addicted and dependent state.
Because constipation is among the actions of opiates, many agents selected for anti-diarrheal activity, such as 2,2-diphenyl-4-[(4-carbethoxy-4-phenyl)piperidino)butyronitrile, generically known as diphenoxylate, act via one or more of these opioid receptors. Because of the diverse actions mediated by opioid receptors, such agents also have undesirable central nervous system effects and abuse potential. Because of these diverse activities and the potential for abuse, anti-diarrheal opioid drug development has been directed towards identifying compounds in which the potentially beneficial activities are separated from the activities that lead to abuse and dependence.
During the mid to late 1960's, several agents derived from classes of molecules known to have opioid activity were synthesized. These agents were shown to have naloxone reversible suppressant effects in smooth muscle bioassays and were able to readily displace opioid ligands in receptor binding assays. These results indicated that they act via direct or indirect action with opioid receptors. These compounds were designed to be selective anti-diarrheal opioid receptor (believed to be the .mu. receptor) agonists that are substantially free from analgesic and habit-forming activities (see, e.g., Shriver et al. (1987) "Loperamide" in Pharmacological and Biochemical Properties of Drug Substances, Vol. 3, Goldberg, M. E., ed. Am. Pharm. Assoc., Washington, D.C., p. 462).
Compounds, such as loperamide (4-(.rho.-chlorophenyl)-4-hydroxy-N-N-dimethyl-.alpha.,.alpha.-diphenyl-1- piperidinebutyramide hydrochloride), and its analogs were among those synthesized. Loperamide was widely reported to be completely devoid of analgesic effects and CNS effects (see, e.g., Jaffe et al. (1980) Clin. Pharmacol. Ther. 80:812-819) even at relatively high dosages. Subsequent work has demonstrated certain analgesic effects of intraparenterally administered loperamide (see, e.g., Takasuna et al. (1994) Behavioural Pharm. 5:189-195), but none or questionable CNS effects have been demonstrated.
In contrast to conventional opiates, however, loperamide and analogs thereof and other such agents exhibit little or no analgesic effects as measured in acute pain models, such as the tail clip and hot plate tail withdrawal tests, when given systemically (see, e.g., Stahl et al. (1977) Eur. J. Pharmacology 46:199-205; Shriver et al. (1981) "Loperamide" in Pharmacological & Biochemical Properties of Drug ubstances Vol. 3, Goldenberg, Ed., American Pharmaceutical Assn. Press, pp. 461-476; see, also U.S. Pat. No. 3,714,159 and U.S. Pat. No. 3,884,916). This absence of CNS effects, including analgesic effects, is believed to be related to the failure of such compounds to cross the blood brain barrier. This failure is in part due to the extremely high lipid partition coefficient of the compounds. The high partition coefficient results in sequestration of the compound in the lipid membrane. This local absorption is thought to contribute to its failure to cross the blood brain barrier. In support of this conclusion, antinociceptive analgesic action has been observed after direct delivery into the brain (Stahl et al. (1977) Eur. J. Pharmacology 46:199-205).
Peripheral injury and hyperalgesia.
Changes in the milieu of the peripheral sensory terminal occur secondary to local tissue damage. Mild damage (such as abrasions or burns) and inflammation in the cutaneous receptive fields or joints will produce significant increases in the excitability of polymodal nociceptors (C fibers) and high threshold mechanoreceptors (Handwerker et al. (1991) Proceeding of the VIth World Congress on Pain, Bond et al., eds., Elsevier Science Publishers BV, pp. 59-70; Schaible et al. (1993) Pain 55:5-54). This increased excitability leads to increased spontaneous activity (in otherwise silent sensory afferents) and an exaggerated response to otherwise minimal stimuli.
These events have several consequences. First, the magnitude of the pain state in humans and animals is proportional to the discharge rate in such sensory afferent (Raja et al. (1988) Anesthesiology 68:571-590). The facilitated response secondary to the local peripheral injury may lead to an exaggerated pain state simply because of the increased afferent activity. Secondly, spontaneous activity in small sensory afferent causes central neurons in the spinal cord to develop an exaggerated response to subsequent input (Woolf et al. (1991) Pain 44:293-299; Neugebauer et al. (1993) J. Neurosci. 70:1365-1377). Both of these events, secondary to the increased spontaneous activity and reactivity in small sensory afferents generated by the peripheral injury leads to a behavioral state referred to as hyperalgesia (Yaksh, T. L., (1993) Current Opinion in Neurology and Neurosurgery 6:250-256).
Thus, in the instance where the pain response is the result of an exaggerated response to a given stimulus, the organism is hyperalgesic. The importance of the hyperalgesic state in the post injury pain state has been repeatedly demonstrated and this facilitated processing appears to account for a major proportion of the post-injury/inflammatory pain state (see, e.g., Woold et al. (1993) Anesthesia and Analgesia 77:362-79; Dubner et al. (1994) In, Textbook of Pain, Meizack et al., eds., Churchill-Livingstone, London, pp. 225-242).
Certain drug actions may serve to normalize the sensitivity of the organism. Experimental investigations have shown that opiates with an action in the vicinity of the peripheral terminal in injured or inflamed tissue will normalize the activity in afferent innervating inflamed skin (Russell et al. (1987) Neurosci. Lett 76:107-112; Andreev et al. (1994) Neurosci. 58:793-798) and normalize the hyperalgesic threshold (Stein (1988) Eur. J. Pharmac. 155:255-264 Stein (1993) Anesth. Analg. 76:182-191). Opiates, such as morphine, however, when peripherally applied, have a short duration of action and possibly can, if applied at sufficient levels, have effects upon consciousness and respiration. The possible systemic effects, CNS effects and abuse potential render conventional opioids unsuitable for local application and unsuitable as peripheral anti-hyperalgesics. Thus, there is a need for effective anti-hyperalgesics that directly block peripheral sensitization, but that do not have concomitant central nervous system (CNS) effects, including the potential for abuse.
Therefore, it is an object herein to provide anti-hyperalgesics for local and topical application minimal or no CNS effects.